Cannabidiol (CBD)

Alternative names


Current Scheduling Status
Year(s) and type of review / ECDD meetings
Drug Class

Recommendation (from TRS)

Substance identification
Chemically, cannabidiol (CBD) is 2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex- 2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD is one of the naturally occurring cannabinoids found in cannabis plants. It is a 21-carbon terpenophenolic compound that is formed following decarboxylation from a cannabidiolic acid (CBDA) precursor, although it can also be produced synthetically. CBD has two stereoisomers but is normally taken to refer to the naturally occurring (−)-enantiomer. (+)-CBD has been synthesized but has received little attention.

In plants, Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are derived from their acidic precursors Δ9- tetrahydrocannabinolic acid (THCA) and CBDA, respectively. Subsequent decarboxylation of THCA and CBDA via light exposure, heating or ageing, results in Δ9-THC or CBD. Synthetic routes are available to produce CBD, but some of the published methods yield only small amounts. There are several published methods for the analytical detection of CBD in various biological samples.

Ease of convertibility into controlled substances
There is some evidence that CBD can be converted in the laboratory to Δ9-THC, which is controlled under the 1971 United Nations Convention on Psychotropic Substances. The laboratory conversion of CBD to Δ9-THC results in a preparation of uncertain purity. There is limited in vitro evidence that this conversion can occur spontaneously in the presence of acid. Overall, however, there is no evidence that this transformation occurs in humans after oral CBD administration

General pharmacology
In clinical trials and research studies, CBD is generally administered orally as either a capsule or dissolved in an oil solution (for example, olive or sesame oil). Probably due to its poor solubility in water, the absorption of CBD from the gastrointestinal tract is erratic, and the resulting pharmacokinetic profile is variable. CBD is extensively metabolized in the liver and, as a result, bioavailability from oral delivery is estimated to be only 6%. CBD may preferentially accumulate in adipose tissues due to its high lipophilicity. In in vitro models, CBD has been shown to modify concentrations of other drugs through the inhibition of cytochrome P450 (CYP) isozymes, but it is not clear whether the same effects occur with clinical doses.

There are two types of cannabinoid (CB) receptors: CB1, which are primarily located in the central nervous system with some expression in peripheral tissues, and CB2, which can be found in the periphery on cells with immune function, in the gastrointestinal tract, and at low densities in the central nervous system. CBD does not appear to act directly at CB1 receptors, and most studies find no agonist effects at this receptor. CBD also shows low affinity at CB2 receptors.

In human and animal studies, CBD has been shown to have very different effects from those of Δ9-THC. In mice, CBD fails to produce the behavioural characteristics (for example, suppression of locomotor activity, hypothermia, antinociception) associated with CB1 activation, whereas Δ9-THC generates all the effects that occur when CB1 is activated. Neuroimaging studies in humans and animals have shown that CBD has effects that are generally opposite to those of Δ9-THC. In contrast to Δ9-THC, CBD does not affect heart rate or blood pressure under normal conditions. CBD may interact with the endocannabinoid system through indirect mechanisms and several non-endocannabinoid signalling systems as well, but it is not clear which, if any, of these other mechanisms are responsible for any of CBD’s potential clinical or other effects.

In general, CBD has been found to have low toxicity, although studies are limited and not all potential effects have been explored.

Adverse reactions in humans
CBD does not produce the effects that are typically seen with Δ9-THC. CBD has been found to be generally well tolerated with a good safety profile across several controlled and open-label trials investigating its potential therapeutic effects. Adverse events reported in clinical studies investigating the therapeutic possibilities of CBD have included, but have not been limited to, somnolence, decreased appetite, diarrhoea and fatigue.

Dependence potential
It was not possible to identify any reports on controlled studies of the physical dependence potential of CBD in laboratory animals or humans. Tolerance to CBD has not been observed.

Abuse potential
Several laboratory animal studies indicate that CBD does not produce effects common to many drugs of abuse, nor, more specifically, effects comparable to those of Δ9-THC. In particular, unlike other drugs of abuse, it does not activate the mesolimbic dopamine (reward) pathway in the brain or potentiate the effect of rewarding electrical stimulation. CBD fails to show an effect in the conditioned place preference model of reinforcement, and its effects do not resemble those of Δ9-THC in the drug discrimination model of subjective drug effects.

Clinical studies have shown that even high doses of oral CBD do not cause Δ9-THC-like effects (for example, impairment of cognitive and psychomotor function, increased heart rate/tachycardia and dry mouth). When evaluated in healthy volunteers, administration of single oral doses of up to 600 mg of CBD had placebo-like effects on physiological measures and on the scales of the Addiction Research Centre Inventory. In a randomized, double-blind, within- subject laboratory study in recreational cannabis users, CBD produced no significant psychoactive, cardiovascular or other effects at doses up to 800 mg orally. Overall, there is no evidence that oral CBD administration in humans results in clinically relevant Δ9-THC-like subjective or physiological effects. Co- administration of oral CBD does not affect the intensity of Δ9-THC subjective effects. There are no case reports of abuse or dependence relating to the use of CBD.

Therapeutic applications, extent of therapeutic use and
epidemiology of medical use CBD is presently marketed in several countries in combination with Δ9-THC in a 1:1 ratio (Sativex®). CBD is in development for a variety of therapeutic applications including schizophrenia, fragile X syndrome, encephalopathies, childhood absence seizures, neonatal hypoxic–ischaemic encephalopathy and perinatal asphyxia. The clinical use of CBD is most advanced in the treatment of epilepsy. In clinical trials, CBD has demonstrated effectiveness for treating at least some forms of epilepsy, with one pure CBD product (Epidiolex®) found effective in clinical studies of Lennox-Gastaut syndrome (a severe form of epileptic encephalopathy that produces various types of seizures) and Dravet syndrome (a complex childhood epilepsy disorder that has a high mortality rate), which are often resistant to other forms of medication.

In 2015, the US FDA granted fast-track designation for intravenous CBD to treat neonatal hypoxic–ischaemic encephalopathy. The European Commission also granted orphan designation for CBD to be used in the treatment of perinatal asphyxia. Currently there are no other treatments available for these conditions, but there is evidence of the effectiveness of CBD in animal models.

Listing in the WHO Model List of Essential Medicines
Cannabidiol is not listed in the WHO EML (20th list) or the WHO Model List of Essential Medicines for Children (6th list).

Marketing authorizations (as a medicinal product)
One pure CBD product (Epidiolex®) was under consideration for registration at the time of the ECDD meeting. There are several other CBD products in development.

Industrial use
Pure CBD has no legitimate industrial uses.

Non-medical use, abuse and dependence
There are no case reports of abuse or dependence relating to the non-medical use of pure CBD. CBD-based products are, however, used for a variety of medical indications in preparations that are not regulated by pharmaceutical authorities.

Nature and magnitude of public health problems related to
misuse, abuse and dependence No public health problems (for example, driving under the influence of drugs, harm to health or comorbidities) have been associated with the use of pure CBD.

Licit production, consumption and international trade
Licit production for medical research is described in section 6.11 (Marketing authorizations).

Illicit manufacture and traffic and related information
There are no published statistics (for example, country data on seizures of illicit CBD) available.

Current international controls and their impact
CBD is not explicitly specified for inclusion in the schedules of the 1961 and the 1971 United Nations International Drug Control Conventions, nor is it included in the List of precursors and chemicals frequently used in the illicit manufacture of narcotic drugs and psychotropic substances (6) under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988. However, if prepared as an extract or tincture of cannabis it is controlled in Schedule I of the Single Convention on Narcotic Drugs, 1961.

Current and past national controls
Several countries have CBD under some form of regulatory control. However, some have relaxed their control in recent years, in part to make CBD more accessible for medical use or research.

WHO review history
A pre-review of CBD was undertaken during the thirty-ninth meeting of the ECDD in November 2017 following a recommendation from the thirty-eighth ECDD that pre-review documentation on cannabis-related substances, including CBD, be prepared and evaluated at a subsequent Committee meeting. Following its pre-review at the thirty-ninth ECDD meeting, the Committee recommended that extracts and preparations containing almost exclusively CBD be subject to critical review at the fortieth meeting of the ECDD.

CBD is one of the naturally occurring cannabinoids found in cannabis plants. There are no case reports of abuse or dependence relating to the use of pure CBD. No public health problems have been associated with CBD use.

CBD has been found to be generally well tolerated and to have a good safety profile. Adverse effects of CBD use include loss of appetite, diarrhoea and fatigue.

Therapeutic applications of CBD are being researched for a variety of clinical uses. Research in this area is most advanced in the treatment of epilepsy. In clinical trials, one pure CBD product has demonstrated effectiveness for treating some forms of epilepsy, such as Lennox-Gastaut syndrome and Dravet syndrome, which are often resistant to other forms of medication.

CBD is not specifically listed in the schedules of the 1961, 1971 or 1988 United Nations International Drug Control Conventions. However, if prepared as an extract or tincture, it is controlled under Schedule I of the 1961 Single Convention on Narcotic Drugs.

There is no evidence that CBD as a substance is liable to similar abuse or leads to similar ill-effects to substances controlled under the 1961 or 1971 Conventions such as cannabis or Δ9-THC, respectively.

The Committee recommended that preparations considered to be pure CBD should not be scheduled.

ECDD Recommendation

Critical review recommended